Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

• the present invention relates to the discovery that 2-(2-aminoalkylamino)-l,Z-diphenylethanols of the formula wherein R and R are as above with a diamine of the formula wherein R R R and n are as above.
• reaction between compounds of the formulae II and III can be carried out in a manner known per se such as, for example, by utilizing elevated temperatures, preferably reflux temperatures, and an excess of the diamine reactant as solvent.
• optical antipodes of compounds of formula I can be readily obtained by resolution of the racemic form of said compounds in a manner known per se.
• a suitable resolution procedure involves the formation of diastereomeric salts of compounds of formula I with an optically active acid, i.e., diacetone-Z-keto-L- gulonic acidhydrate, selectively crystallizing out one of the diastereomers, then purifying and hydrolyzing this material with base, i.e., dilute sodium hydroxide, to yield the enantiomer.
• the other enantiomer can be isolated from the mother liquors by treatment with another optically active acid, i.e., d-tartaric acid to form the corresponding diastereomer salt which is then purified and hydrolyzed with base as above.
• d-tartaric acid i.e., d-tartaric acid
• Both enantiomers of the compounds of formula I exhibit topical antiinflammatory activity.
• Preferred compounds of formula I are obtained where R and R are in the para position, or particularly preferred when R and R both are hydrogen; R is hydrogen and n is 2.
• A'particularly preferred compound of the invention is erythro-2-(2-aminoethylamino )-l ,Z-diphenylethanol.
• lower alkyl is meant to include straight and branched chain saturated hydrocarbon radicals having from 1 to 7, preferably 1 to 4, carbon atoms.
• Suitable lower alkyl radicals include methyl, ethyl, n-propyl, i-propyl, n-butyl, n-hexyl and n-heptyl. Methyl is a most preferred lower alkyl radical.
• halogen is meant to include chloro, bromo, iodo and fluoro radicals, most preferably chloro.
• the compounds of the invention form acid addition salts with conventional pharmaceutically acceptable acids, i.e., inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, or organic acids such as citric acid, acetic acid, succinic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like
• organic acids such as citric acid, acetic acid, succinic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• Topical dosage forms of the present invention will contain from 0.01 to 20 weight percentpreferably 1 to weight percent of the compounds of formula I.
• the topical dosage forms can be ajelly, cream, lotion, oil, solution, emulsion, or any other conventional form for applying medication to the skin obtained by admixing the present compounds with. known pharmaceutical topical carrier materials.
• Such compositions can be submitted to conventional pharmaceutical expedients such as sterilization and/or can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers and the like. They can also contain other therapeutically useful materials.
• a hot solution of g. of (rac-.)erythro-2-(2- aminoethylamino)-l,Z-diphehylethanol was added 18 g. of diacetone-Z-keto-gulonic acid hydrate (DAG) and the solution left at room temperature overnight.
• DAG diacetone-Z-keto-gulonic acid hydrate
• the original filtrate from the DAG salt was concentrated in vacuo to dryness and the base was liberated as above.
• the enriched base (4.2 g.) melted at 134C.
• the reaction mixture was cooled, and poured into ice cold dilute sodium hydroxide-and extracted with methylene chlo ri'de.
• the org'an 'iclayer was separated, dried and concentrated in vacuo tb'dryness.
• the residue 32 g. was dissolved in a smallamount of methanol and an excess of ethanolic hydrogen chloride was added.
• the precipitated hydrochloride (20 g.) was separated by filtration.
• a second crop (7 g. of hydrochloride was obtained from the filtrate. After several recrystallization of the first crop frommethanol apure hydrochloride (3.7 g. meltingat 276-9C. was obtained.
• the second crop of hydrochloride from the above reaction was purified and treated in the same manner as the first crop.
• This hydrochloride melted at 248252C.
• the erythro-2-(2-arninoethylamino)-2- (4-chlorophenyl)-l-phenylethanol(2 g.) formed colorless needles melting at 91"2C.
• EXAMPLE 3 Erythro-2-( 2-aminoethylamino)-2-phenyll -(p-tolyl ethanol
• a solution of 16.6 g. of trans-4-methyl-stilbene oxide in m1. of ethylenediamine was refluxed for 20 hours.
• the reaction mixture wascooled, poured into ice cold dilute sodium hydroxide and extracted with ether.
• the organic layer was separated, dried and concentrated in vacuo to dryness.
• the residue was dissolved in a small amount of methanol and an excess of ethanolic hydrogen chloride was added.
• the precipitated hydrochloride was separated by filtration. After several recrystallizations from methanola-pure hydrochloride was obtained melting'at 2678C.
• EXAMPLE 4 Erythro-2-(3-aminopropylamino )-l,Z-diphenylethanol
• a solution of 20 g. of trans-stilbene oxide in 60 ml. of 1,3-propanediamine was refluxed for 24 hours.
• the reaction mixture was poured into ice water and extracted with methylene chloride.
• the organic extract was washed with water, dried and concentrated in vacuo to dryness.
• the residue (24 g.) was crystallized from a mixture of tetrahydrofuran and ether to give 17 g. of product melting at 99-100C. After recrystallization from the same solvent mixture the pure product formed colorless needles with the same melting point.
• EXAMPLE 7 The topical antiinflammatory activity of a compound of the invention in direct comparison with dexamethasone is shown in a topical antiinflammatory test based on inhibition of cantharidin induced irritation of rat ear skin. The results of this test are summarized below in Table 1.
• EXAMPLE 6 1 Ch 1 R CD 21 d 1d 1 d ar es 1ver.. ay 0 ma e rats were use Erythro'z'1N'methyl'N'Q'ammoethyl)ammo]'l2'
• the treatment vehicle comprised 0.1 -ml.- of ethanoldlphenylethanol /acetone/ether (1-2-3 by volume) plus 20 percent col- A solution of 20 g. of trans-stilbene oxide in 35 ml. methylethylenediamine was refluxed for 16 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic extract was washed with water, separated, dried and concentrated in vacuo to dryness.
• the first crop of hydrochloride was purified by recrystallization from methanol until the melting point was 263264C. dec.
• a solution of this hydrochloride (6 g.) in ice water was made alkaline with ammonium hydroxide and the mixture was extracted with methylene chloride. The organic extract was separated, dried and concentrated in vacuo to dryness. The residue (4.3 g.) was crystallized from tetrahydrofuran and gave 3.7
• EXAMPLE-8 This example demonstrates the local antiinflammatory activity of a representative compound of the invention in direct comparison with a known clinically useful corticoid compound in the standard cotton pellet test granuloma procedure. The results are summarized in Table Zbelow.
• Dexamethasone and erythro-2-(2-ammoecontinued thylam1no)-l ,2-diphenylethanol were dissolved in etha- 2O nol to yield the desired concentration levels and 0.1 ml.
• Example 10 Erythro-2-( 2-amlnoethylammo)- l ,2-dlphenylethanol of each level was applied to the respective pellets and Ointment the pellets were allowed to air dry at room tempera- Mineral on 1000 ture. Cottonpellets, weighing 34 mg., were used.
• pellet implantation The pellets with adherent granuloma tissue were removed, dried to constant weight and then compared to controls which had been implanted with untreated pellets. The difference in granuloma weights was a measure of the antiinflammatory activity. A linear log dose response relationship was observed for the compound of the invention which was qualitatively similar to that observed for dexamethasone.
• Step 2 added Step 2 to Step 1 and stirred to 55C.
• Step 3 added Step 3 to Step 4 and cooled to room temperature.
• a pharmaceutical composition useful in the topical treatment of an inflammation comprising from 0.01 to 20 weight percent of a compound of the formula wherein R, and R independently are hydrogen, halogen or lower alkyl provided, however, that one of R or R is hydrogen; R is hydrogen or lower alkyl and n is an integer from 1 to 4 and the remainder of said composition comprises conventional pharmaceutical organic or inorganic materials for topical administration.
• composition of claim 4 wherein said compound of formula I is erythro-2-(2-aminoethylamino)- 1,2-diphenylethanol.
• composition of claim 4 in ointment form 6.
• composition of claim 4 in a lotion form.
• composition of claim 4 in a cream form.
• composition of claim 4 in a gel form.

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (15)

Applications Claiming Priority (1)

Publications (1)

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Country Status (15)

Cited By (4)

• 1974
  • 1974-10-10 US US513798A patent/US3928621A/en not_active Expired - Lifetime
• 1975
  • 1975-09-10 ZA ZA00755767A patent/ZA755767B/xx unknown
  • 1975-09-12 IL IL48098A patent/IL48098A/xx unknown
  • 1975-09-15 NZ NZ178688A patent/NZ178688A/xx unknown
  • 1975-09-16 AU AU84871/75A patent/AU8487175A/en not_active Expired
  • 1975-09-24 DE DE19752542610 patent/DE2542610A1/de active Pending
  • 1975-10-03 IE IE2172/75A patent/IE41907B1/en unknown
  • 1975-10-08 LU LU73552A patent/LU73552A1/xx unknown
  • 1975-10-08 FR FR7530780A patent/FR2287220A1/fr not_active Withdrawn
  • 1975-10-08 PH PH17642A patent/PH11505A/en unknown
  • 1975-10-09 DK DK455675A patent/DK455675A/da unknown
  • 1975-10-09 GB GB41434/75A patent/GB1498083A/en not_active Expired
  • 1975-10-09 SE SE7511356A patent/SE7511356L/xx unknown
  • 1975-10-09 BE BE160797A patent/BE834334A/xx unknown
  • 1975-10-10 NL NL7511943A patent/NL7511943A/nl not_active Application Discontinuation

Non-Patent Citations (1)

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